Hepatic aldose reductase drives a Warburg effect-like metabolic reprogramming to promote insulin resistance, fatty liver and obesity

Background & Aims: Emerging evidence suggest that abnormal activation of aldose reductase/the polyol pathway (Ar/PP) is associated with the pathogenesis or development of fatty liver, obesity and metabolic syndrome. However, the underlying mechanisms were unclear. In this study, we investigated the metabolic reprogramming following activation or inhibition of Ar, the first and the rate-limiting enzyme of PP. We also investigated the long-term effects of Ar/PP-mediated metabolic shift in vivo. Methods: Metabolomic analyses were performed with the AB-SCIE QTRAP-5500 LC-MS/MS System for control mouse hepatocytes and hepatocytes stably overexpressing Ar and exposed to 25 mM glucose. Glycolysis stress tests and mitochondrial stress tests were performed using the Seahorse Bioscience Extracellular Flux Analyzer. The in vivo long-term effects of Ar overexpression and inhibition were evaluated in either transgenic mice overexpressing AR or a line of double transgenic mice carrying an Ar-null mutation and an Agouti-yellow Ay mutation. Results: Abnormal activation of Ar in hepatocytes was found to trigger and drive a drastic Warburg effect-like metabolic reprogramming, induce de novo lipogenesis, and alter insulin and AMP-activated protein kinase signaling. In glucose-fed AR-overexpressing transgenic mice, AR activation causes systemic alterations in physiological parameters and the development of overt phenotypes of insulin resistance, fatty liver, obesity. In the yellow obese syndrome mice, Ar deficiency greatly improves Agouti Ay mutation-induced abnormalities. Conclusions: Collectively, the results highlight the important contribution of Ar/PP or the putative pseudo-glycolysis in hepatic metabolic homeostasis and the development of metabolic diseases. These findings have profound implications for the development of therapeutic strategies or drugs against metabolic diseases and cancer.